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The prediction of Overall Survival and Response to 2nd line treatment is a major challenge in treatment of Head and Neck Squamous Cell Carcinoma (HNSCC). Here we used tumor kinetics measured by the Sum of the Largest Diameters (SLD) of the lesions in the patients during the first line to provide interesting predictive metrics for Overall Survival. Using a mechanistic mathematical model, we were able to fit the clinical data of SLD measurements in a HNSCC clinical trial. The data we used consist of 528 patients with 22 baseline clinical feaures. After benchmarking different machine learning algorithms, the Random Survival Forest Algorithm combined with the mechanistic model was able to predict the Overall Survival with a C-index of 0.7 in cross-validation on the train set and 0.67 on the test set. Likewise, the most impacting parameters for the prediction of OS are the parameters resulting from the mathematical model describing the kinetics of tumors (the tumor growth rate and Time to Growth after shrinkage)., La prédiction de la survie globale et de la réponse au traitement de 2e ligne est un défi majeur dans le traitement du carcinome épidermoïde de la tête et du cou (HNSCC pour Head and Neck Squamous Cell Carcinoma). Ici, nous avons utilisé la cinétique tumorale mesurée par la somme des plus grands diamètres (SLD) des lésions chez les patients au cours de la première ligne pour fournir des métriques prédictives intéressantes pour la survie globale. À l'aide d'un modèle mathématique mécaniste, nous avons pu ajuster les données cliniques des mesures SLD dans un essai clinique HNSCC. Les données que nous avons utilisées se composent de 528 patients avec 22 variables cliniques de base. Après avoir comparé différents algorithmes d'apprentissage automatique, l'algorithme de Forêts Aléatoires de Survie (RSF pour Random Survival Forest) combiné au modèle mécaniste a pu prédire la survie globale avec un indice C de 0.7 en validation croisée sur l'ensemble d'entrainement et de 0.67 sur l'ensemble de test. De même, les paramètres les plus impactants pour la prédiction de la Survie Globale sont les paramètres résultant du modèle mathématique décrivant la cinétique des tumeurs (le taux de croissance tumorale et le temps de croissance après rétrécissement).

International audience; Background: Adenoid cystic carcinoma (ACC) accounts for 1% of malignant head and neck tumours [1] and 10% of salivary glands malignant tumours. The main objective of our study is to investigate the prognostic factors influencing the event-free survival (EFS) of patients with ACC. Patients and methods: A multicentre prospective study was conducted from 2009 to 2018. All 470 patients with ACC whose survival data appear in the REFCOR database were included in the study. The main judgement criterion was EFS. Both a bivariate survival analysis using log-rank test and a multivariate using Cox model were performed using the R software. Results: Average age was 55 years. Females accounted for 59.4% of the cohort. The body mass index (BMI) was normal in 86% of cases. Tumours were located in minor salivary glands in 60% of cases. T3/T4 stages represented 58%; 89% of patients were cN0. histological grade III was observed on 21% of patients. The EFS and overall 5-year survival rates were 50% and 85%, respectively. After adjustment, the most significant pejorative prognostic factors were age >= 65 years (hazard ratio [HR] = 1.67), BMI

International audience; PURPOSE:The "PRAVACUR" phase 2 trial (NCT01268202) assessed the efficacy of pravastatin as an antifibrotic agent in patients with established cutaneous and subcutaneous radiation-induced fibrosis (RIF) after head and neck squamous cell carcinoma (HNSCC) radiation therapy and/or radiochemotherapy.METHODS AND MATERIALS:The main inclusion criteria were: NSCC in remission, grade ≥2 cutaneous and subcutaneous neck RIF (National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0), and no current treatment with statins or fibrates. Patients received pravastatin 40 mg/d for 12 months. The primary endpoint was reduction of RIF thickness by more than 30% at 12 months, as measured by cutaneous high-frequency ultrasonography. Secondary endpoints included RIF severity reduction, pravastatin tolerance, and quality of life.RESULTS:Sixty patients with grade 2 (n = 37), grade 3 (n = 22), or grade 4 (n = 1) RIF were enrolled from February 2011 to April 2016. The mean interval between RIF diagnosis and pravastatin initiation was 17.1 months. Pravastatin was stopped before 11 months of treatment in 18 patients (because of grade ≥2 adverse events related to pravastatin in 8 patients [13%]). In the 40 patients in whom pravastatin efficacy was assessed by high-frequency ultrasonography at baseline and at 12 months of treatment, a reduction of RIF thickness ≥30% was observed in 15 of 42 patients (35.7%; 95% confidence interval, 21.6%-52.0%). At the 12-month clinical evaluation, RIF severity was decreased in 50% of patients (n = 21; 95% confidence interval, 34.2%-65.8%), and the patients' self-perception, mood state, and social functioning were significantly improved. Pravastatin was well tolerated, with a very low occurrence of grade 3 toxicities (myalgia, n = 1) and grade 2 toxicities (myalgia/arthralgia or esophagitis, n = 3).CONCLUSIONS:This phase 2 prospective study supports the notion of radioinduced fibrosis reversibility. It showed that pravastatin (40 mg/d for 12 months) is an efficient antifibrotic agent in patients with grade ≥2 cutaneous and subcutaneous fibrosis after HNSCC radiation therapy.

International audience; Head and neck cancers are a leading cause of cancer incidence and mortality, with over 800 000 new cases and 400 000 deaths estimated in 2018 by GLOBOCAN[1]. Over the years, a wide range of randomized controlled trials have been conducted to define the best treatment strategies for each disease site and tumor stage. These trials have evaluated the role of chemotherapy, altered fractionated radiotherapy, targeted therapy or radioprotectants. To help define treatment guidelines, individual patient data meta-analyses were conducted by collaborative groups led by the meta-analysis unit at Gustave Roussy Cancer Center, launched in 1994 by Jean Bourhis and Jean-Pierre Pignon. They have focused on the role of chemotherapy[2,3] or altered fractionation radiotherapy[4] in locally advanced head and neck squamous cell cancers (HNSCC), amifostine[5], and chemotherapy in nasopharyngeal cancer (NPC)[6]. Additional works have studied surrogate endpoints for HNSCC[7] and NPC[8], network meta-analyses for HNSCC[9] and NPC[10]; but also the impact of missing data on trial characteristics[11] or the use of alternative relative efficacy metrics such as the restricted mean survival time difference[12].The aim of this article is to focus on the relevance of meta-analyses today and tomorrow in a world where patients’ and tumors’ genomic profiling and tailored treatment could become the rule. We will concentrate on individual patient data meta-analyses, which is the gold standard for collecting and synthesizing evidence[13]. The medical literature is currently flooded with meta-analyses based on published data. A quick search on Pubmed performed on December 28th 2018 using the keywords “head neck cancer” and the built-in filter “meta-analysis” retrieved 2080 references, with more than 250 new “meta-analyses” performed each year since 2014. A minority of these is synthesizing comparative data prospectively collected, and only a handful is based on individual patient data.

Background Based on the hypothesis of a synergistic effect of the anti-PDL1 avelumab when combined with cetuximab (cetux) and RT, this new combination is tested in a large scale randomized trial against two well established SoC in LA-SCCHN pts. Methods This randomized multicenter phase III trial comprises two cohorts of pts deemed fit (Cohort 1) to receive high dose cisplatin (CDDP 100 mg/m², Q3W) or unfit (Cohort 2) to receive CDDP. The SoC is IMRT (69.96 Gy, 33 fractions) combined with CDDP in Cohort 1 (arm A) and with cetux (arm D) in Cohort 2 (400 mg/m² Day-7 and 250 mg/m² weekly). In both cohorts, experimental (exp) arms are IMRT concomitant with cetux (same schedule as in SoC) and avelumab (10 mg/kg Day-7 and every 2 weeks) followed by avelumab 10 mg/kg bi-monthly for 12 months (arms B and C). The primary objective is to test whether exp arm is superior to SoC for progression-free survival in each cohort, with 400 and 268 pts to be randomized to Cohort 1 and 2 respectively. Monitoring of grade ≥4 acute adverse events (AE) in both exp arms was planned with null and alternative hypotheses of 15% and 35%, 1-sided α error = 0.10, Lan-DeMets α spending function, power 95%. This safety phase was approved by the Independent Data and Safety Monitoring Committee (IDSMC) and planned to be run on the first 41 pts randomized in exp arms, in 3 steps, after 8 weeks follow-up of 14, 27 and 41 pts. Results Between September 2017 and August 2018, 82 pts with LA-SCCHN were randomized including 41 in the exp arms. All pts of exp arms received the entire RT, except one in arm C with early stop after 55 Gy. In exp arms, 36 pts (88%) and 31 pts (76%) received the expected number of avelumab and cetux administrations during RT. In the exp arms, the most common grade ≥3 AE were radiation dermatitis, mucositis and dysphagia. Grade ≥4 AEs occurred in 5/41 (12%) pts in the exp arms (all in arm C), in 3/21 (14%) pts in arm A and 2/20 (10%) in arm D. Only one grade 5 AE occurred in arm A. Conclusions The combination of avelumab, cetuximab and RT is tolerable for pts with LA-SCCHN in the safety phase of this ongoing phase 3 trial and an approval to continue the trial was given by IDSMC. Clinical trial identification NCT02999087. Legal entity responsible for the study GORTEC. Funding Merck Serono. Disclosure Y. Tao: Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (institution): Debiopharma; Research grant / Funding (institution): Pfizer. J. Thariat: Advisory / Consultancy: BMS; Advisory / Consultancy: Nanobiotix. J. Guigay: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Innate pharma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono. J. Bourhis: Advisory / Consultancy: Merck Serono; Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD. All other authors have declared no conflicts of interest.

Sea bass is a major species in Mediterranean aquaculture, and is now being subject to selective breeding programmes for faster growth. In terrestrial species, it was demonstrated that fast growth may be linked to a correlated degradation of fitness traits. In this experiment, we evaluated 600 young sea bass from a factorial mating of 76 sires and 13 dams. The sires were from four genetic groups, wild (W), domesticated (D), and selected for growth (2 groups, M and P). The 600 offspring were submitted to two acute confinement stress challenges at 6 weeks intervals, and plasma cortisol at one hour post stress was measured. The same fish were also submitted to two swimming challenges at a 5 days interval, where the maximum sustained swimming speed ( U max ) of each fish was evaluated. Parentage was assessed by genotyping of 12 microsatellites. 554 fish had both valid parentage and phenotypes. Cortisol had a low repeatability (r = 0.30 between the two successive measurements) while repeatability was moderate for U max (r = 0.62). However, genetic correlations between successive measurements were very high (> 0.96) for both traits, indicating that successive measurements were related to the same trait. Heritability was moderate for mean post-stress cortisol (h 2 = 0.34 ± 0.09) and U max (h 2 = 0.48 ± 0.08). When U max was expressed in m.s − 1 , it was negatively correlated to cortisol (r A = − 0.48 ± 0.08) and weakly correlated to body weight (r A = 0.12 ± 0.16), but figures changed when it was expressed in Body Lengths.s − 1 (h 2 = 0.55 ± 0.08, r A = − 0.10 ± 0.19 with cortisol and r A = − 0.64 ± 0.07 with body weight, respectively). Cortisol was moderately negatively correlated with body weight (r A = − 0.36 ± 0.18). The four lines did not differ for cortisol or U max , but when U max was expressed in BL.s − 1 it tended to be lower in the two selected lines — which were also significantly larger. However, this is likely due to a phenotypic decrease of relative U max with increasing body size. We conclude that selection for growth and/or domestication should not impact maximum sustained swimming speed in the European sea bass, but may tend to favour animals with low cortisol responsiveness. These traits could be used to orientate functional capabilities other than productivity in sea bass. Statement of relevance We estimate heritability of cortisol stress response and (for the first time) in European sea bass, as well as their correlations with growth. We show moderate correlations, and no correlated response to selection for growth. We also provide methods to evaluate these traits on large number of fishes. This can be useful to monitor and design breeding programmes.

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells., peer-reviewed

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International audience; OBJECTIVES: To compare virological effectiveness in patients who continued on a virologically successful first-line boosted protease inhibitor (PI)-containing combination antiretroviral therapy (cART) regimen or who switched to a PI-free cART including efavirenz, nevirapine or abacavir. METHODS: From the French Hospital Database on HIV, we selected 439 patients with undetectable viral load (VL) on a first-line boosted PI-containing cART regimen who switched to a PI-free combination including efavirenz, nevirapine or abacavir. Each of these patients was matched with three patients who continued to take their first-line cART regimen, on the basis of gender, age, CD4 cell count, VL, date of cART initiation and the duration of VL undetectability. Time to virological failure (VF) was analysed with Kaplan-Meier curves and Cox models. RESULTS: The 12 month probabilities of VF were 3.7% and 5.7% in non-switch and switch patients, respectively, and 3.9%, 7.2% and 9.0% in patients switching to efavirenz-, nevirapine- and abacavir-containing cART, respectively. After adjustment, only patients switching to abacavir-containing cART had a higher risk of VF than non-switch patients (adjusted hazard ratio, 1.99; 95% confidence interval, 1.05-3.79). CONCLUSIONS: Switching from a virologically successful first-line boosted PI-containing cART regimen to a non-nucleoside reverse transcriptase inhibitor-containing cART regimen containing either efavirenz or nevirapine is virologically safe, while switching to abacavir-containing cART should be avoided.

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International audience; In this study, the consequences of the exposure of rainbow trout (Oncorhynchus mykiss) to a brief stress during early development were explored on the later response of fingerlings to stress. Firstly, we analyzed the ontogeny of cortisol production and that of the initial cortisol response to stress in developing fish. It is only at the eyed stage that the embryos started to produce some basal cortisol. The HPI (hypothalamic-pituitary-interrenal axis) was however not functional before hatching, as exposure of the embryos to a stress did not trigger any cortisol response. A cortisol response to an acute Stress was detected 9 days after hatching. In a second set of experiments, we showed that a very brief stress applied at 3 different early stages (eyed, hatching, and yolk resorption) reduced the later cortisol response to stress of 5-month-old fingerlings. This reduction is not likely to be due to alterations in the fish interrenal sensitivity because the 5-month-old fingerlings responded to ACTH treatment (only one dose tested) within the same magnitude as the fish that were not stressed during early development. An experimentally induced increase in egg cortisol just after fertilization also induced a reduction in stress sensitivity of 5 month old fingerlings, which was dose-dependent This study shows for the first time that the responsiveness of the corticotrope axis in 5-6 months old rainbow trout was influenced both by early stress exposure and by initial egg cortisol levels. Whether the HPI was functional or not at the time the initial stress was applied only had a small influence on the later unambiguous effect of early stress exposure. (C) 2008 Elsevier Inc. All rights reserved.

International audience; Although effects of hypoxia and, in a lower extent, effects of hyperoxia, have been widely studied, very few data is available regarding the effect of oxygen concentration around normoxia. Moreover, the effect of rearing oxygen level around normoxia on flesh quality, and a possible interaction with stress at slaughter, have never been investigated. Rainbow trout were reared during 18 weeks up to pan size (mean weight 400 g) at 76, 98 or 117% of oxygen saturation. Afterwards they were slaughtered according to two procedures: a minimal stress (NS group), or after a 15 min confinement stress (S group). Fish characteristics (weight, condition factor, fat-meter value, plasma cortisol level, hepato-somatic index, and hepatic glycogen content) and quality criteria of fillets (color, initial muscle pH, and muscle glycolytic potential) were recorded at slaughter time, whereas mechanical resistance, ultimate pH and dry matter content of the flesh were measured at 24 h and 48 h post-mortem. Muscle fiber size was analyzed on histological samples from white and red muscles. In our study, rearing oxygen level had no impact on the morphological characteristics of the fish except a higher hepato-somatic index and hepatic glycogen content for trout reared at 97% oxygen saturation. Rearing oxygen level affects slightly flesh quality at the lowest oxygen level (76% saturation) with a lower force for low deformation mechanical resistance measurement in the anterior part of the fillet. Stress before slaughter highly increased plasma cortisol concentration (by more than 18 in mean), and decreased fat-meter values (of 14% in mean) and the mean diameter of red muscle fibers (of 6.4% in mean). Stress before slaughter also decreased fillet lightness (L*, -1.1 unit), yellowness (b*, -0.76 unit), and initial pH (-0.15 unit) of the flesh but had no effect on ultimate pH measured at 24 or 48 h post-mortem. Stress before slaughter induced a softer flesh as shown by lower mechanical resistance at high deformation measured on samples from both anterior and caudal part of the fillet. The post-mortem measurement time (24 or 48 h) was the main factor affecting the mechanical resistance of the flesh, with a significant softening of the flesh between 24 and 48 h. Nor oxygen level, nor slaughter stress affected the size of white muscle fibers. No major interaction between rearing oxygen level and slaughter stress was formally demonstrated.

International audience; The present paper describes the main procedures used to slaughter fowl, pigs, calves and adult cattle, sheep, and farmed fish, starting on the farm and ending with the death of the animal at the abattoir. It reviews the currently known causes of stress, indicated by behavioural and physiological measurements on the animal level, and by post-mortem muscle metabolism. During the pre-slaughter period, psychological stress is due to changes of environment, social disturbances and handling, and physical stress is due to food deprivation, climatic conditions, fatigue, and sometimes pain. The exact causes of stress depend, however on the characteristics of each species, including the rearing system. For fowl, bird catching and crating, duration and climatic conditions of transport and of lairage and shackling are the main known pre-slaughter stress factors. For pigs, stress is caused by fighting during mixing of pens, loading and unloading conditions, and introduction in the restrainer Handling and novelty of the situation contribute to the stress reactions. For veal calves and adult cattle, disruption of the social group, handling, loading and sometimes unloading conditions, fatigue, novelty of the situation and for calves mixing with unfamiliar animals are known stress factors. Gathering and yarding of extensively reared lambs and sheep causes stress, particularly when shepherd dogs are used. Subsequent transport may induce fatigue, especially if sheep are commercialised through auctions or markets. In farmed fish, stress is predominantly related to environmental aspects such as temperature, oxygen, cleanliness of the water and, to a certain extent, stocking density and removal of the fish from the water If transport and lairage conditions are good and their durations not too long, they may allow pigs, calves and adult cattle, sheep, and fish to rest. For certain species, it was shown that genetic origin and earlier experience influence reactions to the slaughter procedure. Stunning techniques used depend on the species. Pigs and fowl are mostly electrically or gas-stunned, while most adult cattle are stunned with a captive bolt pistol. Calves and sheep may be electrically stunned or with a captive bolt pistol. Various stunning methods exist for the different farmed fish species. Potential causes of stress associated with the different stunning procedures are discussed. The paper addresses further consequences for meat quality and possible itineraries for future research. For all species, and most urgently for fish, more knowledge is needed on stunning and killing techniques, including gas-stunning techniques, to protect welfare.

International audience; BACKGROUND: Transfusion of red blood cells (RBCs) has been associated with immunomodulatory effects. Persistence of donor cells in the recipient may be contributive. STUDY DESIGN AND METHODS: A randomized single-center trial was conducted to compare microchimerism and immune responses in 35 patients undergoing cancer surgery and transfused perioperatively with either unmodified RBCs (UN-RBCs, n = 18) or leukoreduced RBCs (LR-RBCs, n = 17). Biologic parameters included microchimerism assessment peripheral blood mononuclear cell (PBMNC) phenotyping, cytokine production by stimulated PBMNCs, FoxP3 gene expression, and T-cell repertoire (TCR) analysis. RESULTS: Microchimerism was documented in 8 of 18 patients after UN-RBC transfusion while absent after LR-RBC transfusion (0/17; p = 0.001). After UN-RBC transfusion, microchimerism was associated with increased interleukin (IL)-10 production (p = 0.02), reduced TCR alteration (p = 0.04), and reduced CD56+ cell counts (p = 0.02) when compared to recipients without evidence for microchimerism. FoxP3 gene expression did not differ significantly between both treatment groups nor with the presence or absence of microchimerism in the UN-RBC group. Finally, after an initial early decrease after surgery and transfusion, IL-12 production increased and more significantly so after UN-RBC transfusion versus LR-RBC transfusion (p = 0.05). CONCLUSION: UN-RBC-induced microchimerism is associated with specific immunomodulatory effects in cancer patients who received transfusions during surgery.

International audience; Measuring HPA axis activity is the standard approach to the study of stress and welfare in farm animals. Although the reference technique is the use of blood plasma to measure glucocorticoid hormones (cortisol or corticosterone), several alternative methods such as the measurement of corticosteroids in saliva, urine or faeces have been developed to overcome the stress induced by blood sampling itself. In chronic stress situations, as is frequently the case in studies about farm animal welfare, hormonal secretions are usually unchanged but dynamic testing allows the demonstration of functional changes at several levels of the system, including the sensitization of the adrenal cortex to ACTH and the resistance of the axis to feedback inhibition by corticosteroids (dexamethasone suppression test). Beyond these procedural aspects, the main pitfall in the use of HPA axis activity is in the interpretation of experimental data. The large variability of the system has to be taken into consideration, since corticosteroid hormone secretion is usually pulsatile, follows diurnal and seasonal rhythms, is influenced by feed intake and environmental factors such as temperature and humidity, age and physiological state, just to cite the main sources of variation. The corresponding changes reflect the important role of glucocorticoid hormones in a number of basic physiological processes such as energy metabolism and central nervous system functioning. Furthermore, large differences have been found across species, breeds and individuals, which reflect the contribution of genetic factors and environmental influences, especially during development, in HPA axis functioning. Usually, these results will be integrated with data from behavioral observation, production and pathology records in a comprehensive approach of farm animal welfare.

National audience; Despite progress made in recent years, the pre-slaughter period remains stressful for animals. Current slaughter procedures involve regrouping and mixing animals, removing them from their familiar environment and introducing them into unfamiliar settings, transporting, handling, and depriving them of food, and are sometimes associated with poor quality of surroundings. These often cause stress, which can be both physical (fatigue, hunger, pain, discomfort) and psychological (fear, social stress). Stunning techniques are sometimes poorly controlled or unsuitable. Slaughter procedures cause behavioural, physiological and metabolic responses that are used to determine the animal's stress levels. To improve animal welfare, further knowledge of the exact causes of stress is required. The possible negative effects of stress responses on meat quality are also briefly addressed.; Malgré les progrès de ces dernières années, la période de pré-abattage est une source de stress pour les animaux. Les procédés d’abattage nécessitent des regroupements et des mélanges d’animaux, l’enlèvement du milieu habituel et l’introduction dans des environnements non familiers, le transport, la manipulation par l’homme et le jeûne, et entraînent parfois des mauvaises conditions d’ambiance. Ils sont souvent générateurs de stress d’origine physique (fatigue, faim, douleur, inconfort physique) et psychologique (peur, stress social). Les techniques d’étourdissement sont parfois mal maîtrisées ou mal adaptées. Ces procédés entraînent des réponses comportementales, physiologiques et métaboliques qui sont utilisées pour évaluer le niveau de stress de l’animal. Afin de mieux respecter le bien-être animal à l’abattage, il est nécessaire d’élargir nos connaissances des causes de stress. L’effet négatif que peuvent avoir ces réponses sur les qualités des viandes est succinctement abordé.

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International audience; Despite a consensus on the need for Pneumocystis carinii pneumonia (PCP) prophylaxis for HIV-infected patients with fewer than 200 CD4+ lymphocytes/mm3, the number of cases of PCP has remained stable, and about 70% involve patients who are not receiving prophylaxis. The aim of this study was to determine why these patients are not covered by prophylaxis. It was based on a retrospective analysis of semidirective interviews with 32 patients who developed PCP while not receiving prophylaxis. The reasons given were a lack of knowledge of risk factors for HIV infection, the fear of HIV testing, unawareness of the existence of PCP prophylaxis, a refusal to see a doctor in the absence of symptoms, unwillingness to be monitored and in four cases a failure of the doctor to prescribe prophylaxis.

In this study, the expression of several genes involved in cortisol synthesis in head kidneys, the site of cortisol production, and in the rainbow trout (Oncorhynchus mykiss) was examined in response to two different acute stressors and an acute ACTH treatment. mRNAs levels of the "steroidogenic acute regulatory" (StAR) sterol transport protein, which transports cholesterol to the inner mitochondrial membrane as well as cytochrome P450 cholesterol side chain cleavage (P450 S C C ) were determined in head kidney (containing the interrenal tissue). In one experiment, we also quantified 3-β-hydroxysteroid dehydrogenase (3B-HSD) and cytochrome P450 1 1 β (11B-H) mRNAs. The presence of these four transcripts in the head kidney was confirmed by Northern blot analysis. For each stress condition, mRNA levels were quantified by quantitative or real-time RT-PCR. The results of these two methods were highly correlated. An acute stress induced by capture, short confinement (2 min), and anesthesia (3 min) resulted in significant elevation of plasma cortisol (30-fold higher than controls) and an increase in levels of StAR and P450 S C C mRNAs 3 h post-stress. When fish were submitted to an acute stress caused by 5 min of chase with a net in a tank, plasma cortisol reached a peak within 1 h, but after 3 h, levels were only 5-fold higher in stressed trout than in controls and no variations in the expression of StAR, P450 S C C , 3B-HSD, and 11B-H were observed whatever the time post-stress. One hour after acute ACTH stimulation (5TU/kg), plasma cortisol level was 4-fold higher than in control trout and no changes in StAR and P450 S C C mRNAs levels were detected. The data suggest that the high levels of cortisol after stress need an activation of genes involved in cortisol synthesis, but lower levels do not. Futhermore, under these three test conditions, we always found a strong positive correlation between mRNA levels of StAR and P450 S C C , in contrast to what has been described in mammals. Consequently, the absence of transcription activation with low increase in cortisol levels suggests that other levels of regulation, particularly activation of pre-existing proteins, govern cortisol production.

Evaluating the ecological impact of an oil spill is a complex issue requiring coherently articulated examination of the sequence of interactions that link the cell, where contaminants exert their effects, to the ecosystem, where interactions with human activities arise. This sequence of interactions traverses the frontiers between scientific disciplines (chemistry, toxicology, physiology, and fisheries ecology). Using the common sole (Solea solea L.) as a model species for the coastal habitats polluted by the "Erika" oil spill, our research project attempted to define indices of functional integrity that characterised the consequences of fuel exposure at the different biological levels. The coupling of field observations with experimental laboratory work revealed how functional alterations which are readily observable within individuals and their organs are progressively obscured as investigation progresses towards more complex organisational levels. Some of the approaches and indices are proposed as instruments for evaluating the impact of contamination by hydrocarbons., L'évaluation des conséquences écologiques d'une marée noire est un problème complexe qui requiert un examen articulé et cohérent de la chaîne d'interactions qui relie l'échelle cellulaire, à laquelle agit le contaminant, à l'échelle écosystémique, où se situent les interactions avec les activités humaines. Cette chaîne d'interactions traverse les frontières des disciplines scientifiques (chimie, toxicologie, physiologie, écologie halieutique). En prenant la sole (Solea solea L.) comme espèce cible - espèce caractéristique des habitats côtiers pollués par l'"Erika" - le programme de recherche ECTOPHY est une première tentative de mise en place d'une approche multidisciplinaire visant à définir, valider et mettre en relation des indicateurs d'intégrité fonctionnelle caractérisant les différents niveaux biologiques. Le couplage d'observations in situ avec des expositions en milieu contrôlé a montré que des pertes de fonctionnalité évidentes et durables à l'échelle de l'individu sont masquées à l'échelle de la population. Certaines des approches (in situ ou expérimentale) et certains des indicateurs testés peuvent être proposés comme instruments utilisables dans le cadre d'évaluation d'impact de pollutions par des hydrocarbures.

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The effects of concentration (5, 50, and 500 microg/L) and duration (24, 48 h) of exposure to carbofuran, a carbamate insecticide, were assessed on brain catecholamine (norepinephrine [NE] and dopamine), plasma glucose, and hepatic glycogen contents and behavioral activities of goldfish (Carassius auratus). After 24 h of exposure to 50 and 500 microg/L, the level of NE was increased in the olfactory bulbs. The same effect was observed after a 48-h exposure to 500 and 50 microg/L in the telencephalic hemispheres and in the hypothalamus, respectively. An increase in the level of dopamine was also found in hypothalamus after 48 h of exposure to 500 microg/L carbofuran. Plasma glucose increased in concentration after both periods of exposure to carbofuran at 50 and 500 microg/L. Hepatic glycogen concentration decreased after a 48-h exposure to the highest concentration. Behavioral endpoints related to swimming pattern and social interactions were affected after a 24-h exposure to the lowest concentration tested (5 microg/L). The relative sensitivities of these different types of responses to exposure to carbofuran are discussed in light of data on the neurotoxic effects of carbamate and organophosphate insecticides in fish.

In fish, a layer of mucus covers the external body surface contributing therefore, among other important biological functions, to the defense system of fish. The prevention of colonization by aquatic parasites, bacteria and fungi is mediated both by immune system compounds (IgM, lysozyme, etc.) and by antibacterial peptides and polypeptides. We have recently shown that only the hydrophobic components of crude epidermal mucus of fresh water and sea water fish exhibit strong pore-forming properties, which were well correlated with antibacterial activity [N. Ebran, S. Julien, N. Orange, P. Saglio, C. Lemaitre, G. Molle, Comp. Biochem. Physiol. 122 (1999)]. Here, we have isolated novel glycosylated proteins from the hydrophobic supernatant of tench (Tinca tinca), eel (Anguilla anguilla) and rainbow trout (Oncorhynchus mykiss) mucus. The study of their secondary structure was performed by circular dichroism and revealed structures in random coil and alpha-helix in the same proportions. When reconstituted in planar lipid bilayer, they induced the formation of ion channels. This pore-forming activity was well correlated with a strong antibacterial activity (minimal inhibitory concentration < 1 microM for the three proteins) against both gram-negative and gram-positive bacteria. Our results suggest that fish secrete antibacterial glycoproteins able to kill bacteria by forming large pores (several hundreds to thousands of pS) in the target membrane.

La cinetique d'anesthesie de truites arc-en-ciel (Oncorhynchus mykiss) avec de l'Aqui'S® a ete suivie sur des animaux de differents poids (9, 25 et 200 g). La vitesse d'anesthesie augmente avec la dose d'Aqui'S® utilisee. Aucune mortalite n'a ete observee lorsque les concentrations utilisees sont inferieures a 60 ml/m3 d'eau pour une duree d'anesthesie inferieure a 30 min. La cinetique de reveil est egalement dose dependante. L'anesthesique a egalement ete teste avec succes sur des truites fario (Salmo trutta) de 190 g. L'anesthesie de truites arc-en-ciel dans le bassin d'elevage (sans peche des animaux) avec une concentration de 40 ml d'Aqui'S® /m3 d'eau ou dans un bac (apres une peche rapide des animaux) avec une concentration de 100 ml d'Aqui'S® /m3 d'eau ne provoque pas d'augmentation des concentrations plasmatiques de Cortisol par rapport a celles mesurees chez des animaux anesthesies avec une concentration de 1 l de 2-phenoxyethanol/m3 . Lors d'un transport de truites arc-en-ciel a une densite de 145 kg/m3 pendant 6 heures, l'addition d'Aqui'S® ou de 2-phenoxyethanol a l'eau des cuves permet d'avoir des animaux en legere sedation. Les concentrations plasmatiques de Cortisol sont significativement plus faibles que celles mesurees chez les animaux transportes sans anesthesique. Cependant, ces concentrations sont significativement superieures a celles des animaux restes dans le bassin d'elevage. Les animaux transportes sous sedation legere ont repris l'alimentation plus rapidement que les animaux non anesthesies. Ces travaux, bien que preliminaires, montrent que l'Aqui'S® permet d'obtenir le meme type d'anesthesie qu'avec le 2-phenoxyethanol pour un prix de revient legerement inferieur.

The aim of the present study was to assess a potential link between confinement stress and prolactin (PRL), the hormone responsible for adaptation to a hypoosmotic environment in freshwater-adapted tilapia (Oreochromis niloticus). The effect of stress on plasma levels of the two tilapia PRL forms, tiPRLI (or tiPRL188) and tiPRLII (or tiPRL177), was examined along with the effects on plasma levels of cortisol and growth hormone (GH). In a preliminary study, various sampling protocols (immediate sampling; sampling one by one; anesthesia at 0.5, 1, 2 ml/liter phenoxyethanol) were tested for their ability to modify basal plasma PRL and cortisol. In fish sampled within 1 min of capture (immediate sampling), no changes in the plasma levels of these hormones were observed, whereas when fish were sampled one at a time, PRL levels did not change but cortisol levels were modified. The immediate sampling protocol was used to study the effects of 1 hr confinement stress, which induced a large increase in plasma cortisol levels as well as increases tiPRLI and tiPRLII levels with kinetics similar to those of cortisol. In contrast, plasma tiGH levels significantly decreased after 1 hr confinement. When this stress situation was removed, plasma cortisol and tiPRL levels decreased and plasma GH levels increased. Two and one-half hours later, values were not significantly different from those measured in control fish. In tilapia exposed to 24 hr confinement stress, similar changes in hormone levels were observed. However, after 24 hr confinement, only cortisol levels were significantly different from those measured in control fish. None of these stress conditions significantly changed plasma chloride levels. Together, these results indicate that both PRL and GH have important roles in the adaptive response of freshwater-adapted tilapia to confinement stress.

ISTA III : International Symposium on Tilapia in Aquaculture, 3., Abidjan (CIV), 1996; National audience

ISTA III : International Symposium on Tilapia in Aquaculture, 3., Abidjan (CIV), 1996; National audience

Prolactin (PRL) receptors in gill tissue have been analyzed in tilapia (Oreochromis niloticus) after transfer from fresh water (FW) to brackish water (BW). This study has indicated the presence of only one class of tilapia PRL (tiPRL) receptor whatever the salinity. After transfer, however, the percentage of specific binding of the two forms of tiPRL (tiPRLI and tiPRLII) increased significantly. Scatchard analysis of tiPRLI binding indicated an increase in receptor affinity, an effect which was not accompanied by any change in receptor specificity. Transfer to BW also caused the number of tiPRL receptors to increase rapidly, remaining high in fish adapted to BW for 28 days. Based on the sharp reduction in plasma tiPRLI and tiPRLII levels after transfer to BW, one possible explanation may be that tiPRL itself is an important factor regulating the number of free receptors. This hypothesis finds support in the fact that the number of tiPRL receptors also increased in hypophysectomized fish reared in FW. However, the absence of change in receptor affinity after hypophysectomy suggested that yet other factors are involved in tiPRL receptor regulation during the transfer from FW to BW. The paradoxically high numbers of tiPRL receptors in the gills of BW-adapted tilapia, even though PRL is known to be a FW-adapting hormone, is discussed with regard to the environment in which tilapia live. Journal of Endocrinology (1995) 145, 213–220

National audience

National audience